The objective of this Program is to investigate image-guided radiotherapy technology to enable safe delivery of more aggressive dose regimens through a combination of biological imaging for improved target delineation and implementation of an integrated and clinically practical system of image-guided adaptive radiation therapy (IGART). IGART uses daily onboard imaging, including 3D CT, coupled with online 3D/4D IMRT adaptive replanning to dramatically reduce treated tissue volumes while simultaneously reducing the uncertainty of dose delivery to extended primary and regional tumor targets. This will allow us to more precisely target dose-per-fraction escalation only to regions known to harbor primary tumor and nodal metastases while reducing early and late sequelae by normal tissue avoidance. We propose to develop IGART initially for three patient populations: locally advanced malignancies of the cervix, prostate, and lung, where the literature supports improved outcomes by dose escalation to both primary and regional disease targets. Novel deformable image registration and reconstruction methods developed in Project 1 will allow mapping of targets delineated on biological imaging studies onto daily treatment CT studies and tracking of trajectories of tissue voxels through a course of IGART therapy. Project 2 will characterize and minimize dose-calculation errors on deforming anatomies; and develop probabilistic IMRT planning tools for optimally managing residual errors. Project 3 will conduct clinical studies of cervical and prostate cancer patients to quantify patient setup and tissue deformation uncertainties and to optimize strategies for estimating the daily anatomy, performing adaptive replanning, and to integrate brachytherapy and IMRT into the IGART process. Project 4 will utilize clinical studies to develop and investigate a 4D IGART system to account for quasiperiodic intrafraction breathing motion variations along with interfraction anatomic changes. In support of the projects, Core A will develop a novel layered image management and software development infrastructure and a QA paradigm for addressing the unique error pathways and logistical constraints posed by online IGART while Core B will provide administrative, biostatistical, and biomodeling support.